Vitamin D ameliorates diethylnitrosamine-induced liver preneoplasia: A pivotal role of CYP3A4/CYP2E1 via DPP-4 enzyme inhibition.

Growing evidence has indicated that vitamin D (Vit D) regulates cell proliferation and differentiation in cancer cells. Accordingly, the present study was conducted to investigate the possible beneficial effects of Vit D on diethylnitrosamine (DEN)-induced liver preneoplasia. The effect of Vit D on HepG2 cells was investigated using MTT assay. Additionally, liver preneoplasia was induced in Swiss male albino mice by giving overnight fasted animals 5 consecutive doses of DEN (75 mg/kg/week). Oral treatment with Vit D (200 IU/kg/day) was initiated either 2 weeks before DEN (first protocol) or 1 week after the first dose of DEN injection (second protocol). At the end of the experiment, tissue levels of GGT, DPP-4, TNF-α, IL-6, CYP2E1, and CYP3A4 were also estimated. Moreover, the histopathological study of liver tissue and immunohistochemical detection of GST-P, PCNA, and NF-κB were performed. Vit D exerted a significant cytotoxic effect on HepG2 cells via significantly increasing BAX, p53, and BAX/Bcl2 ratio, and significantly decreasing Bcl2 mRNA expression. In both in vivo protocols, Vit D was capable of normalizing relative liver weight, PCNA, altered hepatocellular foci, and ductular proliferation. Moreover, Vit D significantly reduced the DEN-induced elevation of AST, ALT, ALP, GGT, DDP-4, TNF-α, IL-6, CYP2E1, liver DNA damage, GST-P, NF-κB, nuclear hyperchromasia/pleomorphism, cholestasis, and inflammatory cell aggregates, but significantly increased CYP3A4 content. In conculsion, current results reflect the potential impact of Vit D in the management of early stages of liver cancer.

A randomized clinical trial to assess the effect of zinc and vitamin D supplementation in addition to hypertonic saline on treatment of acute bronchiolitis.

BACKGROUND: Bronchiolitis, the most common cause of hospitalization in infancy has not yet a definitive treatment. This study was conducted to assess the effect of Zinc and vitamin D on treatment of infants with bronchiolitis. METHODS: In this double blind, randomized clinical trial, 94 infants aged 2 to 23 months, admitted in Mousavi Hospital in Zanjan, Iran, with the diagnosis of acute bronchiolitis were randomly assigned into 3 groups. The control group was only treated with hypertonic saline. The two case groups received either 100 unit/kg/day of Vitamin D or 20 mg/day of zinc in addition to hypertonic saline. Wheezing, duration of hospital stay, cough, cyanosis, respiratory distress and the respiratory rate in the first, third and seventh day of hospitalization were evaluated. RESULTS: There was no significant difference between groups in terms of age, sex, weight, passive smoking, wheezing, oxygen saturation, cyanosis and type of delivery. On the third day of hospitalization, the respiratory rate/min in the control group, the groups receiving vitamin D and zinc were 45.2 ± 10.7, 37.8 ± 3.9 and 41.1 ± 9.1 respectively and the result of repeated measure analysis didn't show any significant difference between the 3 groups (P = 0.562). Duration of hospitalization in the group receiving Vitamin D or zinc and in controls were 4.2 ± 2.6, 4.4 ± 2.2 and 5.1 ± 2.4 days respectively and this difference was not significant. Zinc receiving patients did not differ from the control group regarding to respiratory rate, cyanosis and wheezing. CONCLUSION: Vitamin D or zinc administration was not effective in reducing respiratory rate in children with bronchiolitis. Trial registration This project was approved by the Institutional Ethics Committee (IR, ZUMS.REC.1396.50), and registered on IRCT (IRCT20131217015835N7).

Clinical and molecular characterization of Chilean patients with X-linked hypophosphatemia.

We report the most comprehensive clinical and molecular characterization of XLH patients performed in Chile. We show high prevalence of musculoskeletal burden and pain, associated with significantly impaired physical capacity and quality of life, with many relevant complications presenting more frequently than previously reported in cohorts from developed countries. INTRODUCTION: Our current understanding of the clinical presentation and natural history of X-linked hypophosphatemia (XLH) comes mainly from cohorts from developed countries, with limited data on the clinical and genetic abnormalities of XLH patients in South America. OBJECTIVE: To describe the clinical, biochemical, and molecular presentation of patients with XLH in Chile. METHODS: Patients with XLH referred by endocrinologist throughout Chile were included. Demographic data and clinical presentation were obtained from a clinical interview. Surveys were applied for quality of life (QoL), pain, and functionality. FGF23 was measured by ELISA, and genetic testing was performed. Imaging studies were conducted to assess skeletal and renal involvement. RESULTS: We included 26 patients, aged 2-64 years, from 17 unrelated Chilean families. All pediatric patients but only 40% of adults were receiving conventional therapy, while 65% of all patients had elevated alkaline phosphatase. All patients had mutations in PHEX, including 5 novel variants. Radiographic skeletal events (RSE) and enthesopathies in adults were frequent (34% and 85%, respectively). The duration of treatment was associated with fewer RSE (p < 0.05). Most adults reported pain and impaired QoL, and 50% had impaired physical capacity. The number of enthesopathies was associated with worse pain and stiffness scores (p < 0.05). CONCLUSION: Chilean patients with XLH have a high prevalence of musculoskeletal burden associated with pain and impaired physical capacity and QoL, especially in adults who were generally undertreated. These data identify a significant unmet need, inform our understanding of the current status of patients, and can guide care for XLH patients in similarly socioeconomically defined countries.

Association of serum 25(OH)Vit-D levels with risk of pediatric fractures: a systematic review and meta-analysis.

The association between the risk of fractures and suboptimal vitamin D (Vit-D) status remains controversial in children. This meta-analysis suggested that serum 25(OH)Vit-D levels were lower in pediatric cases with fractures. 25-hydroxyvitamin D (25(OH)Vit-D) levels less than 50 nmol/L were associated with increased fracture risk in children. INTRODUCTION: This study aimed to assess the association between serum 25(OH)Vit-D and the risk of fractures in children, and to explore the sources of heterogeneity and investigate their impact on results. METHODS: Systematic review and meta-analysis were conducted for observational studies comparing serum 25(OH)Vit-D levels between fracture and non-fracture pediatric cases. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: Analysis on 17 case-control and 6 cross-sectional studies (2929 fracture cases and 5000 controls) suggested that 25(OH)Vit-D was lower in fracture cases than in controls (pooled mean difference (MD) = - 3.51 nmol/L; 95% confidence interval (CI): - 5.60 to - 1.42) with a heterogeneity (I2) of 73.9%. The sensitivity analysis which merged the case-control studies that had a NOS score ≥ 4 showed a pooled MD of - 4.35 nmol/L (95% CI: - 6.64 to - 2.06) with a heterogeneity (I2) of 35.9%. Pooled odds ratio of fracture in subjects with 25(OH)Vit-D ≤ 50 nmol/L compared to subjects with 25(OH)Vit-D > 50 nmol/L was 1.29 (95% CI: 1.10 to 1.53; I2 < 1%). CONCLUSION: This study indicated that serum 25(OH)Vit-D levels were lower in pediatric patients with fractures. 25(OH)Vit-D ≤ 50 nmol/L was associated with increased fracture risk in children.

25-Hydroxy cholecalciferol, anti-Müllerian hormone, and thyroid profiles among infertile men.

BACKGROUND AND AIM: We examined the relationship among vit.D3, AMH, FT3, FT4, and TSH, in addition to the serum levels of reproductive hormones (FSH, LH, prolactin, and free testosterone), in oligoasthenoteratozoospermia and azoospermia patients in a cohort of infertile men from Egypt to establish a clinical marker/cause-effect relationship. METHODS: This cross-sectional cohort study was carried out on 301 men (105 males with oligoasthenoteratozoospermia and 96 males with azoospermia), in addition to 100 controls. Measurements of serum vit.D3, AMH, FT3, FT4, and TSH levels, in addition to reproductive hormone assays, were performed on all included subjects, using ELISA kits. RESULTS: Overall, results showed significantly lower serum levels of vit.D3 in infertile men than in the controls, with a greater decrease observed in men with azoospermia than in oligoasthenoteratozoospermia patients, (p < .05 for all). Significantly higher serum TSH and FSH levels and significantly lower serum free testosterone levels were observed in males with azoospermia than in males with oligoasthenoteratozoospermia and the controls (p < .05 for both). There were no significant differences between the studied groups in terms of AMH, FT3 or FT4 levels. LH levels were negatively correlated with TSH levels and positively correlated with AMH levels among men with oligoasthenoteratozoospermia, while among men with azoospermia, LH levels were positively correlated with vit.D3 levels (p < .05 for all). CONCLUSION: Decreased Vit.D3 could play a role in male infertility, in addition to abnormal thyroid function, which needs further investigation.

Serum Vitamin D levels and Vitamin D supplementation do not correlate with the severity of chronic eczema in children.

BACKGROUND: Eczema is one of the most common chronic inflammatory skin diseases, affecting about 20% of children. The pathogenic mechanisms of eczema are still not fully understood, and current treatment of moderate-severe eczema is often difficult. Recently, it has been suggested that Vitamin D plays a key role in this disease, even if mechanisms are only partially known. OBJECTIVE: The purpose of our study was to assess the 25-Hydroxyvitamin D serum levels in a pediatric population suffering from chronic eczema (IgE-mediated and non-IgE-mediated), and to correlate these phenotypes with the SCORAD severity and selected clinical and biological parameters. Moreover, we aimed to evaluate whether a supplementation of Vitamin D3 could affect the same clinical and laboratory parameters. METHODS: 89 children with chronic eczema were enrolled in the study. Severity of eczema was assessed with the SCORAD index. Past and present history was taken, and patients were divided into two groups according to the state of sensitization. According to a randomization schedule, the enrolled children were assigned to the following groups: supplementation group, which received a daily oral Vitamin D3 supplementation (2000 IUs) for 3 months; control group which received no supplementation. RESULTS: Vitamin D concentrations in patients with moderate and severe eczema were not statistically different from Vitamin D concentration detected in the serum of patients with mild eczema. Furthermore, we did not find any correlation between Vitamin D levels, total IgEs and SCORAD index, both in the Sensitized and in the Not-Sensitized group. The Vitamin D3 supplementation did not influence the SCORAD severity or the total IgEs concentration. CONCLUSION: To our knowledge, our study is the first one that shows no correlation between serum levels of Vitamin D, eczema severity and IgE sensitization in a pediatric population suffering from chronic eczema.

Cardioprotective effect of vitamin D3 on cisplatin-induced cardiotoxicity in male mice: role of oxidative stress.

Cisplatin (CP) is a chemotherapy drug used in a broad spectrum of cancer. The current study investigated the protective effect of vitamin D3 (vit-D3) on CP-induced cardiotoxicity. Forty-two male Balb-c mice (20-25 g) were divided into seven groups (GP), 6 per/group were included: GP1 was considered the control group, GP2 received a single dose of I.V. injection of cisplatin (10 mg/kg). Seven days before cisplatin injection on GP3 and GP4 as pre-treatment, vit-D3 was injected I.P. with the doses of 500 IU/kg and 1000 IU/kg, respectively. GP5 and GP6 were considered the treatment groups, were injected cisplatin (10 mg/kg, I.V), and 15 days later, received vit-D3 (500 IU/kg and 1000 IU/kg, I.P) for 7 days. GP7 was the positive control group, which received vit-D3 at a dose of 500 IU/kg (I.P.) for 7 days. Tissues samples and blood serum were collected for biochemical and histopathological investigations. CP injection significantly increased (p < 0.001) LDH, Troponin I, CK-MB, malondialdehyde (MDA), and nitric oxide (NO) levels, but total antioxidant capacity (TAC) levels were significantly reduced. Histological findings showed cardiac muscle rupture, myocardial fiber necrosis, edema, and pyknotic nuclei, indicating cardiac damage. In both pre-treatment and treatment protocol, vit-D3 could improve the histological and biochemical parameters and prevented from the CP toxicity. Vit-D3 significantly could prevent the CP cardiotoxicity in pre-treatment groups, and partially improve the damage of chemotherapy in treatment group. However, further research is necessary to establish the potential of vit-D3 in preventing or ameliorating cisplatin-induced cardiotoxicity.

Male Lrp5A214V mice maintain high bone mass during dietary calcium restriction by altering the vitamin D endocrine system.

Environmental factors and genetic variation individually impact bone. However, it is not clear how these factors interact to influence peak bone mass accrual. Here we tested whether genetically programmed high bone formation driven by missense mutations in the Lrp5 gene (Lrp5A214V) altered the sensitivity of mice to an environment of inadequate dietary calcium (Ca) intake. Weanling male Lrp5A214V mice and wildtype littermates (control) were fed AIN-93G diets with 0.125%, 0.25%, 0.5% (reference, basal), or 1% Ca from weaning until 12 weeks of age (ie, during bone growth). Urinary Ca, serum Ca, Ca regulatory hormones (PTH, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3)), bone parameters (µCT, ash), and renal/intestinal gene expression were analyzed. As expected, low dietary Ca intake negatively impacted bones and Lrp5A214V mice had higher bone mass and ash content. Although bones of Lrp5A214V mice have more matrix to mineralize, their bones were not more susceptible to low dietary Ca intake. In control mice, low dietary Ca intake exerted expected effects on serum Ca (decreased), PTH (increased), and 1,25(OH)2D3 (increased) as well as their downstream actions (ie, reducing urinary Ca, increasing markers of intestinal Ca absorption). In contrast, Lrp5A214V mice had elevated serum Ca with a normal PTH response but a blunted 1,25(OH)2D3 response to low dietary Ca that was reflected in the renal 1,25(OH)2D3 producing/degrading enzymes, Cyp27b1 and Cyp24a1. Despite elevated serum Ca in Lrp5A214V mice, urinary Ca was not elevated. Despite an abnormal serum 1,25(OH)2D3 response to low dietary Ca, intestinal markers of Ca absorption (Trpv6, S100g mRNA) were elevated in Lrp5A214V mice and responded to low Ca intake. Collectively, our data indicate that the Lrp5A214V mutation induces changes in Ca homeostasis that permit mice to retain more Ca and support their high bone mass phenotype.

Optimizing peak bone mass (PBM) is critical for strong bones and osteoporosis prevention. Both genetics and dietary factors like calcium (Ca) contribute to PBM. The goal of this research study was to determine how dietary Ca intake and genetics interact with each other to impact bone mass. Lowering dietary Ca in control mice causes hormonal changes that increase intestinal Ca absorption and reduce urinary Ca loss to protect bone; but this process fails when dietary Ca becomes too low. However, mice with genetically programmed high bone mass could maintain high bone mass even when challenged with Ca deficient diets. This protection is because the high bone mass mice maintain higher serum Ca, have altered production and utilization of Ca-regulating hormones, and have increased molecular indicators of intestinal Ca absorption and kidney Ca retention. Our findings are important because they demonstrate how a genetic program that increases bone formation can drive improved efficiency of Ca utilization to accommodate the increased need for Ca deposition into bone. We believe that our preclinical study provides important proof-of-principle support for the concept of personalized recommendations for bone health management.

Burosumab treatment of X-linked hypophosphatemia patients: interim analysis of the SUNFLOWER longitudinal, observational cohort study.

X-linked hypophosphatemia (XLH) is a genetic disease that results in excessive FGF23, chronic hypophosphatemia, and musculoskeletal abnormalities, with affected patients experiencing symptoms such as bone pain, bone deformity, fracture, and pseudofracture. Burosumab is a fully human monoclonal antibody that binds to FGF23, improving lowered serum 1,25(OH)2D and phosphate levels in patients with XLH. There are insufficient data on the use of burosumab, its safety, and the outcomes of treated patients in a real-world setting. The SUNFLOWER (Study of longitUdinal observatioN For patients with X-Linked hypOphosphatemic rickets/osteomalacia in collaboration With Asian partnERs) study is an ongoing longitudinal, observational cohort study of patients with XLH in Japan and South Korea. Enrollment occurred between April 2018 and December 2020. This interim analysis compared the background characteristics of patients who received burosumab with those who did not, and assessed improvements in biomarkers, physical and motor function, health-related quality-of-life (HRQOL) and other patient-reported outcome (PRO) measures, as well as the safety of burosumab treatment in 143 Japanese patients from 15 institutions over 6 mo. The patients had a median [interquartile range] age of 17.5 [11.0, 38.8] yr and 98 (68.5%) were female. Among patients aged <18 and ≥18 yr, 40/73 (54.8%) and 25/70 (35.7%) received burosumab, respectively. More patients aged ≥18 who received burosumab had bone pain at baseline vs those not treated with burosumab (6/25, 24.0% vs 2/45, 4.4%, p=.021). Patients treated with burosumab had improved serum phosphate and 1,25(OH)2D levels; moreover, rickets severity and HRQOL/PRO measures, such as pain, appeared to improve over 6 mo of burosumab treatment, and no new safety concerns were identified. This study identified trends in the background characteristics of patients with XLH who receive burosumab in real-world clinical practice. Furthermore, the results support the use of burosumab therapy in real-world settings.

Risk factors for hip and vertebral fractures in chronic kidney disease: the CRIC study.

Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population. In a cohort study of 3939 participants in the chronic renal insufficiency cohort (CRIC), we used Cox regression to test associations of putative risk factors with the composite of first hip or vertebral fracture assessed using hospital discharge codes. Mean age was 58 years, 45% were female, 42% were Black, and 13% were Hispanic. There were 82 hip and 24 vertebral fractures over a mean (SD) 11.1 (4.8) years (2.4 events per 1000 person-years [95% CI: 2.0, 2.9]). Measured at baseline, diabetes, lower body mass index (BMI), steroid use, proteinuria, and elevated parathyroid hormone (PTH) were each associated with fracture risk after adjusting for covariates. Lower time-updated estimated glomerular filtration rate (eGFR) was associated with fractures (HR 1.20 per 10 mL/min/1.73m2 lower eGFR; 95% CI: 1.04, 1.38) as were lower time-updated serum calcium and bicarbonate concentrations. Among time-updated categories of kidney function, hazard ratios (95% CI) for incident fracture were 4.53 (1.77, 11.60) for kidney failure treated with dialysis and 2.48 (0.86, 7.14) for post-kidney transplantation, compared with eGFR ≥60. Proton pump inhibitor use, dietary calcium intake, measures of vitamin D status, serum phosphate, urine calcium and phosphate, and plasma fibroblast growth factor-23 were not associated with fracture risk. In conclusion, lower eGFR in CKD is associated with higher fracture risk, which was highest in kidney failure. Diabetes, lower BMI, steroid use, proteinuria, higher serum concentrations of PTH, and lower calcium and bicarbonate concentrations were associated with fractures and may be modifiable risk factors.

People with chronic kidney disease are at high risk of fractures. Our research assessed the relationship between several patient characteristics and the risk of fractures in 3939 patients with chronic kidney disease. We found that the following characteristics were associated with a higher risk of a hip or spine fracture: having diabetes, lower body mass index, use of steroid-containing medications, lower kidney filtration rate ("eGFR"), higher amounts of protein spilled in the urine, lower calcium and bicarbonate levels, and higher parathyroid hormone levels. Future studies should assess if improving these characteristics decreases the risk of fractures in patients with chronic kidney disease.

Structural and molecular imaging-based characterization of soft tissue and vascular calcification in hyperphosphatemic familial tumoral calcinosis.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder caused by deficient FGF23 signaling and resultant ectopic calcification. Here, we systematically characterized and quantified macro- and micro-calcification in a HFTC cohort using CT and 18F-sodium fluoride PET/CT (18F-NaF PET/CT). Fourier-transform infrared (FTIR) spectroscopy was performed on 4 phenotypically different calcifications from a patient with HFTC, showing the dominant component to be hydroxyapatite. Eleven patients with HFTC were studied with CT and/or 18F-NaF PET/CT. Qualitative review was done to describe the spectrum of imaging findings on both modalities. CT-based measures of volume (eg, total calcific burden and lesion volume) and density (Hounsfield units) were quantified and compared to PET-based measures of mineralization activity (eg, mean standardized uptake values-SUVs). Microcalcification scores were calculated for the vasculature of 6 patients using 18F-NaF PET/CT and visualized on a standardized vascular atlas. Ectopic calcifications were present in 82% of patients, predominantly near joints and the distal extremities. Considerable heterogeneity was observed in total calcific burden per patient (823.0 ± 670.1 cm3, n = 9) and lesion volume (282.5 ± 414.8 cm3, n = 27). The largest lesions were found at the hips and shoulders. 18F-NaF PET offered the ability to differentiate active vs quiescent calcifications. Calcifications were also noted in multiple anatomic locations, including brain parenchyma (50%). Vascular calcification was seen in the abdominal aorta, carotid, and coronaries in 50%, 73%, and 50%, respectively. 18F-NaF-avid, but CT-negative calcification was seen in a 17-year-old patient, implicating early onset vascular calcification. This first systematic assessment of calcifications in a cohort of patients with HFTC has identified the early onset, prevalence, and extent of calcification. It supports 18F-NaF PET/CT as a clinical tool for distinguishing between active and inactive calcification, informing disease progression, and quantification of ectopic and vascular disease burden.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder in which patients develop sometimes large debilitating calcifications of soft tissues and blood vessels. It is caused by deficient fibroblast growth factor-23 that leads to high phosphate levels, which contributes to the calcifications. The calcifications and manifestations of this disorder have not been well characterized. We determined the mineral composition of the calcifications to be hydroxyapatite. Capitalizing on the fact fluoride can be integrated into hydroxyapatite, we used radiolabeled sodium fluoride PET/CT scans (18F-NaF PET/CT) to characterize and quantify the calcifications in 11 patients. Eighty-two percent of the patients had calcifications, with the largest located at the hips and shoulders. Micro-calcifications were found in the blood vessels of most patients, including children. The technique also enabled us to differentiate between active vs stable calcifications. This first systematic assessment of calcifications in patients with HFTC showed the utility of 18F-NaF PET/CT as a tool to identify and quantify calcifications, as well as distinguish between active and stable calcifications. This approach will inform disease progression and may prove useful for measuring response to treatment.

Preclinical development of EXT608, an investigational parathyroid hormone derivative with extended half-life for the treatment of hypoparathyroidism.

Hypoparathyroidism, a deficiency of parathyroid hormone (PTH), results in hypocalcemia, hyperphosphatemia, and hypercalciuria. The disease is poorly controlled by calcium and vitamin D supplements or native PTH(1-84) replacement therapy. A version of PTH is being developed using D-VITylation technology, whereby vitamin D is conjugated to a therapeutic peptide, which confers a long plasma half-life by virtue of binding to the abundant vitamin D binding protein (DBP). D-VITylation of PTH caused no reduction in activity at the PTHR1 receptor, and resulted in a plasma elimination half-life of 7-15 h in rats and 24-32 h in cynomolgus monkeys. Analysis of steady-state pharmacokinetics as a function of dose showed flat profiles with smaller peak:trough ratios at low doses, indicative of slower subcutaneous absorption. In thyroparathyroidectomized (TPTx) rats, PTH(1-34)-vitamin D conjugates restored serum calcium and phosphate levels into the normal range over the 24 h dosing period, and increased bone turnover markers and reduced bone mineral density. Urinary calcium was initially elevated, but normalized by the end of treatment on day 27. In healthy monkeys, a single dose of PTH(1-34)-vitamin D conjugates elevated serum calcium levels above the normal range for a period of 24-48 h while simultaneously reducing urinary calcium. Therefore, the lead compound, EXT608, is a promising candidate as a therapeutic that can truly mimic the endogenous activity of PTH and warrants further study in patients with hypoparathyroidism.

Tumor-induced osteomalacia: A systematic literature review.

Introduction: Tumor-induced osteomalacia (TIO), is a rare acquired paraneoplastic syndrome characterized by defective bone mineralization, caused by the overproduction of fibroblast growth factor 23 (FGF23) by a tumor. Material and methods: We conducted a systematic review to identify all case reports of TIO, focusing on those associated with mesenchymal tumors. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) consensus, and we included patients with a diagnosis of TIO and histological confirmation of phosphaturic mesenchymal tumors or resolution of the condition after treatment of the tumor. Bibliographical searches were carried out until December 2023 in the Cochrane Library, Medline and Embase, as well as congress abstracts online. Results: We identified 769 articles with 1979 cases reported. Most patients were adults, with a higher incidence on men. Disease duration before diagnosis is a mean of 4.8 years. Most tumors were histologically classified as PMT. Lower limbs were the predominant location. Hypophosphatemia was present in 99.8 % of patients. The FGF23 was elevated at diagnosis in 95.5 %. Resection of the tumor was the treatment of choice in most of patients. After resection, there was a clinical improvement in 97.6 % of cases, and serum phosphorus and FGF23 levels returned to normal ranges in 91.5 % and 81.4 % of the patients, respectively. Conclusion: TIO is usually misdiagnosed with rheumatological or musculoskeletal disorders. The diagnosis should be suspected in patients with hypophosphatemic osteomalacia, and the measurement of serum FGF23 can be useful for diagnosis and management.

The Correlation between Maternal and Neonatal Vit D (25(OH)D) Levels in Greece: A Cross-Sectional Study.

BACKGROUND: Few studies have correlated maternal and neonatal Vit D (25(OH)D) levels at birth in Greece. We investigated this potential association, taking into account the administration or not of low doses (400-800 IU) of prenatal Vit D supplements. Our study contributes evidence not only to the small amount of existing literature regarding the above correlation, but also to the topic of maternal and neonatal vitamin D deficiency (VDD) during pregnancy in Mediterranean countries, such as Greece. METHODS: A cross-sectional study was conducted on 248 neonates and their mothers from September 2019 to January 2022. Blood samples of 25(OH)D were studied at the time of delivery. Frequency counts and percentages were registered, and logistic regression was used to investigate the independent factors associated with maternal Vit D status. The Chi-square test and the Pearson coefficient were used to demonstrate a possible association between maternal and neonatal 25(OH)D levels. RESULTS: Our findings show a high prevalence of VDD in Greek women and their newborns at birth. This was observed not only in women who did not receive Vit D supplements, but also in all the study groups, especially in the autumn and winter months. We observed that mothers who received low doses (400-800 IU) of prenatal Vit D supplements increased both their own 25(OH)D concentrations and those of their newborns; however, the latter did not seem to be completely covered by the prenatal administration of Vit D because, although their 25(OH)D concentrations increased, they never reached sufficient 25(OH)D levels, unlike their mothers who reached sufficient concentrations. CONCLUSIONS: Overall, this study highlights the strong association between maternal and neonatal 25(OH)D concentrations at the end of gestation. However, neonates tended to show even lower 25(OH)D concentrations relative to maternal 25(OH)D concentrations. The same phenomenon was observed irrespective of the administration of Vit D supplements during pregnancy. Moreover, this is what was observed concerning the administration of formulations with 400-800 IU of Vit D, which the doctors in our clinic used in the present study. In any case, more clinical studies related to the administration of higher doses of Vit D supplementation to pregnant women would lead to more reliable conclusions. Without a doubt, the measurement of maternal vitamin D status during pregnancy provides opportunities for preventive and therapeutic interventions in the mother-infant pair.

Hypophosphatemic rickets and short stature.

An 18-month-old male presented with gross motor delay and poor growth (weight z-score -2.21, length z-score -4.26). Radiographs showed metaphyseal irregularities suggesting metaphyseal dysplasia and sagittal craniosynostosis. Biochemical evaluation supported hypophosphatemic rickets [serum phosphorus 2.3 mg/dL (reference range (RR) 4.3-6.8), alkaline phosphatase 754 unit/L (RR 156-369)] due to renal phosphate wasting (TmP/GFR 4.3 mg/dL, normal for age 4.3-6.8), with C-terminal fibroblast growth factor 23 (FGF23) 125 RU/mL (>90 during hypophosphatemia suggests FGF23-mediated hypophosphatemia). Treatment was initiated with calcitriol and phosphate. Genetic analysis showed a pathogenic variant of FGF23: c.527G > A (p.Arg176Gln) indicative of autosomal dominant hypophosphatemic rickets (ADHR). Consistent with reports linking iron deficiency with the ADHR phenotype, low ferritin was detected. Following normalization of ferritin level (41 ng/mL) with oral ferrous sulfate replacement, biochemical improvement was demonstrated (FGF23 69 RU/mL, phosphorus 5.0 mg/dL and alkaline phosphatase 228 unit/L). Calcitriol and phosphate were discontinued. Three years later, the patient demonstrated improved developmental milestones, linear growth (length Z-score -2.01), radiographic normalization of metaphyses, and stabilization of craniosynostosis. While the most common cause of hypophosphatemic rickets is X-linked hypophosphatemia, other etiologies should be considered as treatment differs. In ADHR, normalization of iron leads to biochemical and clinical improvement.

Assessing the Evidence for Nonobstetric Risk Factors for Deformational Plagiocephaly: Systematic Review and Meta-Analysis.

BACKGROUND: Plagiocephaly is defined as an asymmetrical distortion of the skull, resulting in an oblique trapezoid or parallelogram head shape. Deformational plagiocephaly (DP) is caused by forces acting on one side of the back of the head, distorting normal skull symmetry. OBJECTIVE: The aims of this systematic review and meta-analysis were to critically assess the evidence for nonobstetric risk factors for DP and to make evidence-based recommendations for reducing the prevalence of DP. METHODS: The selection criterion was studies reporting risk factors for DP. Case reviews, case series, expert opinions, and systematic reviews were excluded. PubMed and Web of Science were searched from August 21, 2010, to August 21, 2022. Publication bias was assessed using funnel plots. Meta-analyses were presented using forest plots. RESULTS: A total of 19 studies (cohort studies: n=13, 68%; case-control studies: n=5, 26%; and cross-sectional studies: n=1, 5%) with a total of 14,808 participants were included. Of the 43 investigated potential nonobstetric factors, 16 (37%) were associated with DP. Of these 16 factors, 12 (75%) had odds ratios (ORs) with 95% CIs not crossing 1: insufficient vitamin D intake (OR 7.15, 95% CI 3.77-13.54), head position preference (OR 4.75, 95% CI 3.36-6.73), bottle-only feeding (OR 4.65, 95% CI 2.70-8.00), reduced tummy time (OR 3.51, 95% CI 1.71-7.21), sleeping position (OR 3.12, 95% CI 2.21-4.39), fewer motor milestones reached by the age of 6 months (OR 2.56, 95% CI 1.66-3.96), obesity (OR 2.45, 95% CI 1.02-5.90), maternal education level (OR 1.66, 95% CI 1.17-2.37), male sex (OR 1.51, 95% CI 1.07-2.12), formula feeding (OR 1.51, 95% CI 1.00-2.27), head circumference (OR 1.22, 95% CI 1.06-1.40), and mechanical ventilation (OR 1.10, 95% CI 1.00-1.14). No evidence of publication bias was detected. CONCLUSIONS: This study provides a comprehensive assessment of the nonobstetric factors associated with DP and presents 11 evidence-based recommendations for reducing its prevalence. The primary limitation is that only publication bias was assessed. TRIAL REGISTRATION: PROSPERO CRD42020204979; https://www.crd.york.ac.uk/prospero/display_record.php? ID=CRD42020204979.

Role of vitamins A, C, D, E in cancer prevention and therapy: therapeutic potentials and mechanisms of action.

Cancer, a leading global cause of mortality, arises from intricate interactions between genetic and environmental factors, fueling uncontrolled cell growth. Amidst existing treatment limitations, vitamins have emerged as promising candidates for cancer prevention and treatment. This review focuses on Vitamins A, C, E, and D because of their protective activity against various types of cancer. They are essential as human metabolic coenzymes. Through a critical exploration of preclinical and clinical studies via PubMed and Google Scholar, the impact of these vitamins on cancer therapy was analyzed, unraveling their complicated mechanisms of action. Interestingly, vitamins impact immune function, antioxidant defense, inflammation, and epigenetic regulation, potentially enhancing outcomes by influencing cell behavior and countering stress and DNA damage. Encouraging clinical trial results have been observed; however, further well-controlled studies are imperative to validate their effectiveness, determine optimal dosages, and formulate comprehensive cancer prevention and treatment strategies. Personalized supplementation strategies, informed by medical expertise, are pivotal for optimal outcomes in both clinical and preclinical contexts. Nevertheless, conclusive evidence regarding the efficacy of vitamins in cancer prevention and treatment is still pending, urging further research and exploration in this compelling area of study.

Co-treatment of Astragaloside IV with Vitamin D in Diabetic Peripheral Neuropathic Rats: Protective Effects and Potential Mechanisms.

OBJECTIVE: The potential mechanism underlying the protective effect of Astragaloside IV (AS-IV) co-treatment with 1, 25-dihydroxy-vitamin D (Vit-D) on neuropathy in diabetic high-fat rats was investigated. METHODS: The rat diabetic hyperlipidemia (DH) model was established via streptozotocin and a high-fat diet (HFD). After co-treatment (of AS-IV and Vit-D at respective doses of 50 mg/kg via oral gavage and 30000 IU/kg via intramuscular injection), blood glucose levels, markers of inflammation and oxidative stress, as well as apoptosis and histopathology were evaluated with appropriate techniques. RESULTS: Co-treatment could effectively reduce blood glucose levels substantially (p< 0.01), improve weight loss, and decrease oral glucose tolerance. Reduced respective sensory and motor nerve conduction velocities in rats were substantially improved (p<0.01) after co-treatment. Also, we observed obvious improvement in DH-induced injured nerve fiber myelin structure and other organ pathologies in co-treated rats. Besides, we observed up-regulated expressions of peroxisomal-proliferator activated receptor-alpha (PPAR-α) and Vit-D receptors (VDR) (p< 0.01) through the western blotting technique. Using the same technique, we also discovered reduced levels of interleukin (IL)1 beta, IL-6, and tumor necrosis factor-alpha, coupled with increased IL-10 and superoxide dismutase levels (p< 0.01). Importantly, co-treatment could effectively exert antioxidative and anti-inflammatory effects. Also, co-treatment resulted in the up-regulation of PPAR-α and VDR expressions, inhibition of the renin-angiotensin-aldosterone system, and promotion of ß-cell sensitivity to insulin. CONCLUSION: The combined application of AS-IV and Vit-D exhibited health effects such as anti-oxidation, regulation of inflammatory factors, and promotion of cell repair, which may be considered as the mechanisms underlying treatment of diabetic peripheral neuropathy and improvement in biochemical indicators.

Development and Validation of Novel Free Vitamin D Equations: The Health Aging and Body Composition Study.

Vitamin D deficiency is prevalent in 25% of Americans. However, 25(OH)D may not be an accurate measure of vitamin D because the majority (85%-90%) of 25(OH)D is bound to vitamin D binding protein (VDBP), which varies by over 30% across individuals. Free 25(OH)D may be a better measure, but it is difficult to measure accurately and precisely. The existing free 25(OH)D estimating equation does not include VDBP phenotypes; therefore, new equations that include this variable may be more accurate. A total of 370 participants in the Health, Aging, and Body Composition Study, a cohort of healthy community-dwelling individuals aged 70-79 years old, underwent VDBP and vitamin D metabolite [25(OH)D, 24,25(OH)2D, 1,25(OH)2D, free 25(OH)D] measurements and were randomly allocated into equation development (two out of three) and internal validation (one out of three) groups. New equations were developed with multiple linear regression and were internally validated with Bland-Altman plots. The mean age was 75 ± 3 years, 53% were female, and the mean measured free 25(OH)D was 5.37 ± 1.81 pg/mL. Three equations were developed. The first equation included albumin, 25(OH)D3, 25(OH)D2, VDBP, 1,25(OH)2D3, and 24,25(OH)2D3. The second equation included all variables in Eq. (1) plus VDBP phenotypes. The third equation included albumin, 25(OH)D3, intact parathyroid hormone, and 1,25(OH)2D3. In internal validation, all three new equations predicted free 25(OH)D values within 30% and 15% of the measured free 25(OH)D concentrations in 76%-80% and 48%-52% of study participants, respectively. Equation (2) was the most precise, with a mean bias of 0.06 (95% limits of agreement -2.41 to 2.30) pg/mL. The existing equation estimated free 25(OH)D within 30% and 15% of measured free 25(OH)D in 43% and 22% of participants, respectively. Free 25(OH)D can be estimated with clinically available biomarkers as well as with more laboratory-intensive biomarkers with moderate precision. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Biological Pathways Associated with Vitamins in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is characterized by early-appearing social communication deficits, with genetic and environmental factors potentially playing a role in its etiology, which remains largely unknown. During pregnancy, certain deficiencies in critical nutrients are mainly associated with central nervous system impairment. The vitamin B9 (folate) is primarily related to one-carbon and methionine metabolism, participating in methyl donor generation. In addition, supplementation with folic acid (FA) is recommended by the World Health Organization (WHO) in the first three gestational months to prevent neural tube defects. Vitamin B12 is related to folate regeneration, converting it into an active form. Deficiencies in this vitamin have a negative impact on cognitive function and brain development since it is involved in myelin synthesis. Vitamin D is intimately associated with Ca2+ levels, acting in bone development and calcium-dependent signaling. This vitamin is associated with ASD at several levels since it has a relation with ASD genes and oxidative stress environment. This review carries the recent literature about the role of folate, vitamin B12, and vitamin D in ASD. In addition, we discuss the possible impact of nutrient deficiency or hypersupplementation during fetal development. On the other hand, we explore the biases of vitamin supplementation studies such as the loss of participants in retrospective studies, as well as multiple variants that are not considered in the conclusion, like dietary intake or auto-medication during pregnancy. In this regard, we aim to contribute to the discussion about the role of vitamins in ASD currency, but also in pregnancy and fetal development as well. Furthermore, stress during pregnancy can be an ASD predisposition, with cortisol as a regulator. In this view, we propose that cortisol is the bridge of susceptibility between vitamin disorders and ASD prevalence.